Abstract Sex differences in the nervous system and in behavior are ubiquitous in the animal kingdom. Beyond their basic biological interest, these differences have important implications for understanding the sex bias that characterizes many mental health and neurological disorders. An intriguing but poorly understood component of nervous system sex differences arises through the actions of hormone-independent, cell-intrinsic neural sex in shaping characteristics of the nervous system. In preliminary work using the nematode C. elegans, we have identified robust sex differences in olfactory behavior that arise through cell-intrinsic, sex-dependent modification of the function of neurons common to both sexes. Understanding the mechanisms that underlie these sex differences has great potential to shed light on similar phenomena acting in the mammalian CNS. In three Specific Aims, we will (1) identify the precise neural foci that regulate sex differences in olfaction, and characterize sex differences in the development and function of these neurons; (2) use a candidate-gene approach as well as targeted microarray studies to identify sex-regulated genes in the core nervous system and determine their functional significance; and (3) characterize the role of C. elegans members of the conserved DM family of sexual regulators, including dmd-3, in generating sex differences in olfaction. Together, this work takes an innovative approach to illuminating the conserved molecular, genetic and neural mechanisms by which neural sex is coupled to sex differences in the development and function of the nervous system. Lay summary Using a tiny soil roundworm, we will examine the genetic and cellular regulation of sex differences in the development and function of the nervous system. These studies will identify genes and mechanisms that may have important roles in human mental health and neurological conditions, such as autism, mood disorders and chronic pain syndrome, that preferentially affect one sex over the other.